This invention relates to pharmaceutical products for use in the treatment of asthma and to deliver devices including the products.
This invention relates to pharmaceutical products for use in the treatment of asthma and to delivery devices including the products.
It has been estimated that asthma affects between 4 and 10 percent of the population, causing distress and alarm to both sufferers and bystanders. Asthma attacks appear to be precipitated in many cases by a number of factors such as exercise or pollutants in the inspired air. Other agents such as pollen and airborne particles may predispose an asthma sufferer to an attack by sensitising the airways. This has led to the belief that effective treatment should include administration of drugs which reduce the sensitivity of asthma sufferers to allergens or which neutralise the allergic reaction.
The lungs and airways of non-asthmatics may contain a natural protective barrier which prevents pollutants and other potential irritants from reaching receptors which would otherwise produce an acute attack. Studies have suggested that it is possible to simulate in the lungs of asthma sufferers the situation in normal lungs by causing surface-active phospholipids (SAPL) to bind to the tissue surface of the lungs, thereby reducing the number of receptors exposed to noxious stimuli and reducing the broncho-constrictor reflex.
SAPLs are used clinically for the treatment of respiratory distress syndrome (RDS) in neonates. In this role, it has been assumed that the SAPL functions by reducing the high surface tension forces at the air-water interface within the alveoli, thereby reducing the pressure needed to expand the lungs, see Bangham et al., Colloids and Surfaces, 10 (1984), 337 to 341. Thus, commercially available formulations of SAPL have been designed co spread rapidly over an air-aqueous interface, thereby reducing what is otherwise a very high surface tension of water.
Limited clinical studies have been carried out to determine the effect of commercial SAPLs marketed for treatment of RDS in neonates on asthmatic subjects,xe2x80x94see Kurashima et al Jap. J. Allergol 1991; 40, 160. This paper reported some amelioration of bronchoconstriction in asthmatic adults using an SAPL obtained by extraction from bovine lungs. In another study on children, also using an SAPL obtained from bovine lungs, no significant changes in lung function or histamine response were found,xe2x80x94see Oetomo et alxe2x80x94American Journal of Respiratory and Critical Care Medicine 153; 1996, page 1148.
EP 0 528 034A describes the use of pulmonary surface active material as an ingredient of an antiasthmatic, which is in the form of a liquid or suspension for injection or spraying into the patient""s air way.
The invention provides a therapeutic combination product for use in the prevention and/or treatment of asthma comprising
(a) a medicament comprising a surface active phospholipid (SAPL) composition in finely divided form, the SAPL including a component which enhances spreading of the medicament over a surface at about normal mammalian body temperature; and
b) an antiasthma drug;
wherein ingredients (a) and (b) are provided in a form for administration together or separately.
It is believed that the finely divided powder of ingredient (a), which preferably comprises at least first and second components, has two important effects:
First, the medicament (a) has surfactant properties, which enable it to spread rapidly over the surfaces of the lungs and air passages. It is an important feature of the present invention that the medicament (a) is in the form of a powder, that is, it is in solid form. The xe2x80x9cdryxe2x80x9d surfactant has a high surface activity. It is believed that, on contact of a first component of the medicament (a) with the mucous within the lungs, the presence of a second component results in a lowering of the melting point of the first component, promoting rapid spreading of the first component over the liquid-air interface as a thin film at body temperature. For example, the normal melting temperature of dipalmitoyl phosphatidyl choline, which is a preferred first component is about 40xc2x0 C., that is, above the normal body temperature. When used in combination with a suitable second component, such as a phosphatidyl glycerol, however, the melting point of the dipalmitoyl phosphatidyl choline can in effect be reduced to below the normal body temperature.
Second, once the surface active medicament is in situ over the surfaces of the lungs and air passages, a component of the composition is thought to migrate across the mucous layer enabling a thin hydrophobic lining or coating co be adsorbed onto the tissue surface. Thus, over and above the surface tension reducing properties mentioned above the medicament of the invention is believed to provide a protective effect by virtue of the adsorbed layer in binding to the epithelium, the phospholipid may mask the irritant receptors which elicit the bronchorestrictor reflex, that is, which cause narrowing of the bronchi.
The medicament (a) is in finely divided solid form. It is believed that, as a consequence of the high surface activity of medicament (a) in that form there results a significant drop in surface tension on contact with the aqueous mucous layer of the lung, giving enhanced effectiveness of ingredient (a) and permitting improved access to the lung surfaces for the antiasthma drug(s) to be administered. Thus, the use of the medicament (a) in combination with an antiasthma drug is believed to enhance the effectiveness of the antiasthma drug.
Moreover, as mentioned above, the binding of the phospholipid component to the lung surface is believed to reduce bronchorestrictor as a consequence of a reduction, in receptor-mediated activity attributable to the masking of irritant receptors. That reduced bronchorestriction acts cumulatively with the anti-bronchorestrictive activity of the antiasthma drug. Thus, in some circumstances it may be possible for dosages of an antiasthma drug to be administered to a given patient to be reduced, as a consequence of the synergistic effect of medicament (a) in enhancing the effectiveness of the antiasthma drug as well as the additional anti-bronchorestrictive activity of medicament (a) itself.
xe2x80x9cFinely dividedxe2x80x9d as used herein means that the material has a particle size distribution which is such that at least a major proportion by weight of the particles are small enough to enter into a patient""s airways and, preferably, deep into the lungs when inhaled. In practice, the first and second components preferably each have a particle size distribution which is such that not less than 90%, by weight, of the particles of those components in combination, and more preferably of each of the first and second components, have a particle size of not greater than 10 xcexcm, and especially of not greater than 5 xcexcm. Advantageously, the median particle size of the combined first and second components, and more preferably of each of the first and second components is not more than 10 xcexcm, and preferably not more than 5 xcexcm. The median particle size may be less than 3 xcexcm, for example, about 1.2 xcexcm. It may be desirable in some circumstances for the particles to have a median particle size of at least 0.5 xcexcm. The size of the particles may be calculated by laser diffraction, or by any other method by which the aerodynamic diameter of particles can be determined. xe2x80x9cMedian particle sizexe2x80x9d as used herein means mass median aerodynamic diameter (xe2x80x9cMMADxe2x80x9d). The MMAD may be determined using any suitable method, for example, using a Multi-Stage Liquid Impinger in accordance with the method described in European Pharmacopoeia (supplement 1999) 2.9.18 (Aerodynamic assessment of fine particles). Alternatively, the size distribution of the particles may be characterised by their volume mean diameter (VMD). Advantageously, the VMD is not more than 10 xcexcm, for example not more than 5 xcexcm, and preferably less than 3 xcexcm. Finely divided dry powders of this kind (which may be described as fumed powders) can be adsorbed onto the surfaces of lung tissue and are believed, in use, to become bound to the epithelium.
A finely divided solid mixture of said first and second components of the medicament (a) may be obtained by size reduction of larger particles by any suitable size reduction method, preferably before mixing. Preferably, the first component of the medicament (a) comprises one or more compounds selected from the group consisting of diacyl phosphatidyl cholines. Examples of suitable diacyl phosphatidyl cholines (DAPCs), are dioleyl phosphatidyl choline (DOPC); distearyl phosphatidyl choline (DSPC) and dipalmitoyl phosphatidyl choline (DPPC). Each of those compounds appears to be capable of forming a thin film or coating on surfaces of the lungs. Most preferably, the first component is DPPC.
The second component may comprise one or more compounds selected from the group consisting of phosphatidyl glycerols (PG); phosphatidyl ethanolamines (PE); phosphatidyl serines (PS); phosphatidyl inositols (PI) and chlorestyl palmitate (CP)
Phosphatidyl glycerol (PG) is believed to be capable of binding to lung tissue and possibly enhancing the binding of the first component and is, therefore, a preferred second component. PG is also a preferred second component because of its ability to form with the first component a very finely-divided, dry powder dispersion in air.
The medicament advantageously comprises a diacyl phosphatidyl choline and a phosphatidyl glycerol. The phosphatidyl glycerol is advantageously a diacyl phosphatidyl glycerol. The acyl groups of the phosphatidyl glycerol, which may be the same or different, are advantageously each fatty acid acyl groups which may have from 14 to 22 carbon atoms. In practice, the phosphatidyl glycerol component may be a mixture of phosphatidyl glycerols containing different acyl groups. The phosphatidyl glycerol is expediently obtained by synthesis from purified lecithin, and the composition of the acyl substituents is then dependent on the source of the lecithin used as the raw material. It is preferred for at least a proportion of the fatty acid acyl groups of the phosphatidyl glycerol to be unsaturated fatty acid residues, for example, mono- or di-unsaturated C18 or C20 fatty acid residues. Preferred acyl substituents in the phosphatidyl glycerol component are palmitoleoyl, oleoyl, linoleoyl, linolenoyl and arachidonoyl. The medicament preferably comprises dipalmitoyl phosphatidyl choline and phosphatidyl glycerol, with the phosphatidyl moiety of the phosphatidyl glycerol advantageously being obtainable from the phosphatidyl moiety of egg lecithin.
The first and second components of the medicament (a) may be present in a weight ratio of from 1:9 to 9:1. Advantageously, the proportion by weight of the first component exceeds that of the second component. Preferably, said first component and said second component are present in a weight ratio of from 6:4 to 8:2. At a weight ratio of about 7:3, the mixture spreads rapidly at a temperature of 35xc2x0 C. or above.
DPPC can be prepared synthetically by acylation of glycerylphosphorylcholine using the method of Baer and Bachreaxe2x80x94Can. J. Of Biochem. Physiol 1959, 37, page 953 and is available commercially from Sigma (London) Ltd. The PG may be prepared from egg phosphatidylcholine by the methods of Comfurions et al, Biochem. Biophys Acta 1977, 488, pages 36 to 42; and Dawson, Biochem J. 1967, 102, pages 205 to 210. When co-precipitated with DPPC from a common solvent such as chloroform, PG forms with DPPC a fine powder which spreads rapidly over the surfaces of the airways and lungs. The most preferred composition of the invention contains DPPC and a phosphatidyl glycerol derived from egg phosphatidyl choline and having a mixture of C16, C18 (saturated and unsaturated) and C20 (unsaturated) acyl groups. One form of that composition is obtainable from Britannia Pharmaceuticals Ltd., 41-51 Brighton Road, Redhill, Surrey, under the trade mark xe2x80x9cALECxe2x80x9d. For use in the device of the present invention, however, it is preferred for the particle size of the mixture to be less than that of xe2x80x9cALECxe2x80x9d in the form in which it is currently obtainable commercially. To obtain a mixture in which the particle size is suitable for use in the device of the invention, the phospholipid components may be dissolved in a suitable solvent, for example ethanol, the solution filtered and vacuum-dried, and the solid product size-reduced to obtain particles of the desired size. During size-reduction, care should be taken to protect the mixture from moisture, oxygen, direct heat, electrostatic charge and microbial contamination.
xe2x80x9cAntiasthma drugxe2x80x9d is used herein to include any drug which has biological activity against asthma. It will be appreciated that, as used herein, xe2x80x9cantiasthma drugxe2x80x9d is to be understood as not including the compositions of the medicament of ingredient (a). The antiasthma drug may comprise one or more respiratory drugs including but not limited to drugs selected from the group consisting of xcex22-agonists, steroids, cromones, antimuscarinic drugs and leukotriene receptor antagonists. The combination product may comprise one or more said antiasthma drugs in an amount of up to 10 parts, especially up to one part by weight per hundred parts by weight of said first and second components, in combination, of the said medicament (a). It will be appreciated that the respiratory drug or drugs should be present in such an amount that each dose delivered by the device contains an effective amount of the drug or drugs.
The combination product may comprise a xcex22-agonist which may be terbutaline, a salt of terbutaline, for example terbutaline sulphate, or a combination thereof or may be salbutamol, a salt of salbutamol or a combination thereof. Salbutamol and its salts are widely used in the treatment of respiratory disease. The active particles may be particles of salbutamol sulchate. Long-acting xcex22 adrenoceptor agonists may be present, for example, formoterol, salmeterol, and salts thereof.
The combination product may comprise an antimuscarinic drug, for example ipatropium bromide.
The combination product may comprise a steroid, which may be, for example, beclomethasone dipropionate, budesonide, triamcinolone acetonide or may be fluticasone. The medicament may comprise other prophylactic drugs, including cromones, for example, sodium cromoglycate or nedocromil. The medicament may include a leukotriene receptor antagonist.
Advantageously, at least ingredient (a) is arranged to be delivered to a patent in the form of at least one individual inhalable dose, the or each individual dose comprising said first and second components of ingredient (a) in a combined amount of at least 10 mg. Whereas phospholipids have been disclosed previously as adjuvants in certain forms of delivery device, the amounts of phospholipid administered in a dose by those previously disclosed devices have been much smaller than those envisaged according to the present invention. In fact, it is preferred in accordance with the present invention for each individual dose to comprise at least 25 mg, and more especially at least 40 mg of said first and second components. The first and second components are substantially non-toxic, and the upper limit of the dosage of ingredient (a) may therefore in general be selected having regard to convenience taking into account matters such as, for example, the comfort of the patient and/or design parameters of the device. In general, however, the device will be suck that it can deliver doses of up to 1000 mg, advantageously up to 500 mg, preferably up to 200 mg, and especially up to 100 mg. Preferably, at least ingredient (a) is arranged for sequential delivery of a multiplicity of inhalable doses.
The products of the invention have the further advantage that the first and second components of the medicament (a) may be of synthetic origin. It has been found undesirable to expose asthmatic patients to proteins of animal origin, because such proteins can have a sensitising effect on such patients, and thus the use of synthetic material has considerable advantages over the use of surfactants of animal origin that may contain animal protein.
Because it is desirable in the present invention to achieve a relatively long term adsorption of the medicament (a) on the lung surface, it is highly desirable that the medicament (or any active components) should not break down in the environment of the lungs. One of the factors which will reduce the life of a lining or coating will be the presence of enzymes, such as phospholipase A, capable of digesting DPPC and/or PG. Such enzymes only attack the laevorotatory (L) form, which constitutes the naturally occurring form. Therefore, the medicament should preferably contain the dextrorotatory (D) form or at least comprise a racemic mixture, which is obtained by synthetic routes. Suitable dispersion devices may employ a propellant such as a halocarbon to form the gas stream and may include a tapered discharge nozzle baffle or a venturi to accelerate particles through a discharge nozzle, and to remove oversized particles. Suitable halocarbons include hydrofluorocarbons, hydrofluorochlorocarbons and fluorochlorocarbons having a low boiling point, such as those marketed under the trade mark xe2x80x9cFreonxe2x80x9d. The medicament may be packaged with a propellant in a pressurised aerosol container within the inhaler. Other inhalers have an impeller which mixes the powder into an air stream and delivers the powder-laden air into the patient""s airways see, e.g. U.S. Pat. No. 5,577,497.
A preferred method and apparatus for administering the medicament (a) involves dispersing the powdered medicament in a propellant gas stream. For example, a pressurised canister of a liquefied gas may be connected to a vial containing the medicament. By releasing controlled amounts of gas from the canister into the vial, increments of the medicament are ejected from the vial as a cloud of powder and may be inhaled by the user. Where compatible with the characteristics of the antiasthma drug to be co-administered, that drug may be introduced into the gas stream, so that it is administered in admixture with the medicament (a). It is envisaged that, in use, one or two inhalable doses of the medicament (a), each dose containing 50 mg, may be administered up to three times daily.
Where the antiasthma drug is to be administered separately and sequentially with the medicament (a) administration of the antiasthma drug may occur as and when required by the patient and the timing of administration may thus be independent of the timing of administration of the medicament (a).
The present invention provides a delivery device for administering to a patient by inhalation a medicament for the prevention or treatment of asthma, the delivery device containing a medicament comprising a surface active phospholipid (SAPL) composition in finely divided form, the SAPL including a component which enhances the spreading of the medicament and the delivery device being capable of delivering of at least one individual dose in an amount of at least 10 mg.
The invention also provides a delivery device for administering to a patient by inhalation a medicament for the prevention or treatment of asthma, the delivery device containing a medicament, the medicament being in finely divided powder form and comprising a first component consisting of one or more phosphacidyl cholines and a second component consisting of one or more compounds selected from the group consisting of phosphatidyl glycerols, phosphatidyl ethanolamines, phosphatidyl serines, phosphatidyl inositols and chlorestyl palmitate, the delivery device being arranged for delivery of at least one individual inhalable dose, the or each individual dose comprising said first phospholipid component and said second component in a combined amount of at least 10 mg.
Furthermore, the invention provides use of (a) a surface active phospholipid (SAPL) composition in finely divided form conjointly with (b) an antiasthma drug in the manufacture of a medicament for the control of asthma.